The Mevalonate Pathway in Streptococcus

Project: Research project

Project Details

Description

Streptococcus pneumonia (SP)takes the lives of nearly 4000 people daily, the majority of whom are children
below the age of five. The organism's ability to evolve resistance mechanisms has produced strains capable
of tolerating our "last line of defense" antibiotics. This laboratory recently discovered that
diphosphomevalonate (DPM), an intermediate in the mevalonate pathway, is a potent allosteric inhibitor of
the SP mevalonate kinase (MK), and that it does not inhibit the human isozyme. The mevalonate pathway is
essential for survival of the organism in mouse lung. DPM and the allosteric site offer a lead compound and
target that provide an opportunity to develop a new class of antibiotics that could help eradicate this disease.
Our preliminary data demonstrate that compounds based on these principles are capable of killing infectious
SP in rich media. This proposal integrates structure, function and synthesis in a project designed to explore
and define the three enzymes that comprise the mevalonate pathway in SP, and,in so doing, provide a basis
for the design and synthesis of antibiotics. The information that this program will create is of considerable
fundamental scientific value. Each of the three enzymes that comprise the pathway is a member of the
GHMP kinase protein superfamily, whose biomedical relevance extends to both orphan diseases and cataract
formation. We have determined the structure of MK from SP, and the structure of the DPM-inhibited
complex with bound substrates is imminent. These structures define the MK-target and will reveal how DPM
binding disrupts chemistry. We've also determined the structure of a ternary complex of phosphomevalonate
kinase (PMK)from SP, which raises intriguing mechanistic issues that emphasize both the unique and
familial structural elements of PMK. Diphosphomevalonate decaboxylase (DPM-DC) is a fascinating
enzyme that decarboxylates DPM via a carbocationic transition-state. We will explore the DPM-DC
mechanism by defining its transition-state structures and monitoring the formation of ligand and intermediate
complexes to create an advanced catalytic paradigm for this mechanistic class.
StatusFinished
Effective start/end date4/1/063/31/12

Funding

  • National Institute of Allergy and Infectious Diseases: $546,517.00
  • National Institute of Allergy and Infectious Diseases: $525,117.00
  • National Institute of Allergy and Infectious Diseases: $557,281.00
  • National Institute of Allergy and Infectious Diseases: $560,335.00
  • National Institute of Allergy and Infectious Diseases: $530,598.00

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.